title: GFPT1-myasthenia: clinical, structural, and electrophysiologic heterogeneity.
abstract: OBJECTIVE
  To identify patients with GFPT1-related limb-girdle myasthenia and analyze phenotypic consequences of the mutations.
  
  
  METHODS
  We performed genetic analysis, histochemical, immunoblot, and ultrastructural studies and in vitro electrophysiologic analysis of neuromuscular transmission.
  
  
  RESULTS
  We identified 16 recessive mutations in GFPT1 in 11 patients, of which 12 are novel. Ten patients had slowly progressive limb-girdle weakness responsive to cholinergic agonists with onset between infancy and age 19 years. One patient (no. 6) harbored a nonsense mutation and a second mutation that disrupts the muscle-specific GFPT1 exon. This patient never moved in utero, was apneic and arthrogrypotic at birth, and was bedfast, tube-fed, and barely responded to therapy at age 6 years. Histochemical studies in 9 of 11 patients showed tubular aggregates in 6 and rimmed vacuoles in 3. Microelectrode studies of intercostal muscle endplates in 5 patients indicated reduced synaptic response to acetylcholine in 3 and severely reduced quantal release in patient 6. Endplate acetylcholine receptor content was moderately reduced in only one patient. The synaptic contacts were small and single or grape-like, and quantitative electron microscopy revealed hypoplastic endplate regions. Numerous muscle fibers of patient 6 contained myriad dilated and degenerate vesicular profiles, autophagic vacuoles, and bizarre apoptotic nuclei. Glycoprotein expression in muscle was absent in patient 6 and reduced in 5 others.
  
  
  CONCLUSIONS
  GFPT1-myasthenia is more heterogeneous than previously reported. Different parameters of neuromuscular transmission are variably affected. When disruption of muscle-specific isoform determines the phenotype, this has devastating clinical, pathologic, and biochemical consequences.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA. selcen.duygu@mayo.edu
authors.forename: Duygu
authors.initials: D
authors.lastname: Selcen
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Shen
authors.forename: Margherita
authors.initials: M
authors.lastname: Milone
authors.forename: Joan
authors.initials: J
authors.lastname: Brengman
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
authors.forename: Feza
authors.initials: F
authors.lastname: Deymeer
authors.forename: Richard
authors.initials: R
authors.lastname: Finkel
authors.forename: Julie
authors.initials: J
authors.lastname: Rowin
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Engel
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000110:Acetylcholinesterase / Q000378:metabolism; D000200:Action Potentials / Q000502:physiology*; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D008297:Male; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D009157:Myasthenia Gravis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000235:genetics / Q000648:ultrastructure; D011729:Pyridostigmine Bromide / Q000494:pharmacology / Q000627:therapeutic use; D011950:Receptors, Cholinergic / Q000378:metabolism / Q000648:ultrastructure; D012519:Sarcoplasmic Reticulum / Q000473:pathology; D055815:Young Adult
chemical_list: D011950:Receptors, Cholinergic; C497511:GFPT1 protein, human; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); D000110:Acetylcholinesterase; D011729:Pyridostigmine Bromide; D000109:Acetylcholine